# Mechanisms of age-related tauopathy > **NIH NIH RF1** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $2,481,635 ## Abstract ABSTRACT In 2014, we proposed criteria for a new category of Alzheimer disease (AD) neuropathological change describing subjects with AD-type neurofibrillary tangles without significant amyloid-beta (Aβ) deposition. This autopsy designation, termed primary age-related tauopathy (PART), is the subject of increasing investigation, with studies suggesting that PART diverges in important ways from AD. There is a critical need to better understand what differentiates PART from other tauopathies and AD, which it mimics clinically and neuropathologically. We are assembling a large collection of brain tissues from aged individuals to enable histopathological, genetic and mechanistic molecular studies. We found that PART diverges pathoanatomically from other tauopathies with an unexpected selective vulnerability of different hippocampal subfields. Our data indicates that PART has genetic risk that partially overlaps with AD, uncovering an association with a locus on chromosome 4 containing JADE1, a multifunctional adaptor protein that regulates cell death. Here, we will expand this work to derive novel histopathological traits from our large collection to identify and validate additional risk alleles for PART and uncover novel mechanisms. Our long-term goal is to elucidate the events that underlie tauopathy through characterization of neurofibrillary changes on the cellular level for correlative clinical, biomarker, genetic, and molecular studies. The objective here is to leverage our unique tissue collection to generate novel pathoanatomical endophenotypes for functional genomic studies. We will deploy both classical and computational histopathological approaches. Our preliminary data indicate that computationally derived features more strongly predict functional impairment compared to the gold standard. Our central hypothesis is that patients with PART have a distinct constellation of cellular and molecular drivers that converge with AD with respect to tauopathy but diverge with respect to Aβ pathology. Our rationale is that better defining the neuropathology of PART will enable clinical and genetic associations that reveal mechanistic insights into neurofibrillary degeneration. We will accomplish our objectives by pursuing the following aims: Aim 1. To identify neuropathological signatures of PART and lay the groundwork for genetic and mechanistic studies. Aim 2. To identify risk alleles for PART. Aim 3. To test the hypothesis that candidate genes associated with PART play a mechanistic role in neurofibrillary degeneration. This research is significant because better delineating the features of PART in human post-mortem tissues will provide valuable insights into the cellular events associated with tauopathies. This project is innovative because it will lead to improved approaches for diagnosis and staging PART that more closely align with clinical symptomatology. This research represents a shift in the way we conceptualize tauopathy in aging, allowing... ## Key facts - **NIH application ID:** 10586796 - **Project number:** 2RF1NS095252-06A1 - **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI - **Principal Investigator:** John Fonda Crary - **Activity code:** RF1 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $2,481,635 - **Award type:** 2 - **Project period:** 2015-09-15 → 2025-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10586796 ## Citation > US National Institutes of Health, RePORTER application 10586796, Mechanisms of age-related tauopathy (2RF1NS095252-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10586796. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*